Project Summary/Abstract Infection with Human Immunodeficiency Virus (HIV) affects an estimated 36.7 million worldwide. In the United States, an estimated 1.1 million people are infected. As the access to antiretroviral treatment (ART) has increased, the population of people infected with HIV live longer. Patients with viral suppression have increased life expectancy. However, compare to age-matched individual without HIV infection, they have shortened lifespan with higher rates of comorbidities, including cardiovascular diseases (CVD). Persistent inflammation and chronic immune activation caused by HIV and likely ART results in a pro-inflammatory state that increases the risk for cardiovascular disease. Though statins have been used to decrease the effects of hyperlipidemia and inflammation on progression of cardiovascular disease, use of statins is underutilized in patients with HIV and falls short of realistic goals for LDL reduction in these high-risk patients. Human CD24Fc, developed by OncoImmune, Inc., is a recombinant fusion protein composed of the extracellular domain of human CD24 and the Fc fragment of human IgG1. CD24 is expressed in wide range of cell types as an important genetic modifier for several autoimmune diseases and inflammation in response to danger- associated molecular pattern (DAMPs). Our published data demonstrated that CD24Fc prevented SIV-infected macaques from developing AIDS through induction of inhibitors of inflammation while suppressing promotors for inflammation and autoimmune disease. Our unpublished data showed that in human CD34+ hematopoietic stem cell-reconstituted mouse HIV model, CD24Fc treatment suppressed production of inflammatory cytokines and reduced activation and loss of CD4 T cells. In a Phase I clinical trial in healthy people, ascending doses of CD24Fc (up to 240 mg) significantly decreased fasting LDL level and induced leptin level in serum. The reduction of fasting LDL by CD24Fc is confirmed in a Phase IIa clinical trial in patients undergo hematopoietic stem cell transplantation for leukemia. The results are consistent with the recently discovered connection between inflammation and metabolic disorders. Based on these preliminary results, we propose that treatment with CD24Fc can fortify negative regulation of innate immune responses, decrease LDL, and thus reduce the risk of cardiovascular disease in HIV patients. To test this hypothesis, we will evaluate, in HIV-infected individuals, the safety and efficacy of CD24Fc in normalizing lipid metabolism, reducing T cell activation and viral reservoir. Sixty-four patients aged over 50 with HIV infection who are virally suppressed on antiretroviral therapy for over 2 years will be randomized in a 1:1 ratio to receive either 240mg of CD24Fc or placebo for 12 weeks, with a 24-week follow-up period. We will evaluate the safety and tolerability of the drug as well as the changes in LDL and other cellular and soluble inflammatory parameters with CD24Fc treatment and perform nuclear imaging studies to evaluate changes in myocardial perfusion and function with CD24Fc treatment. This clinical trial will enroll an HIV cohort with 78% of African American. The study will uncover critical knowledge in our understanding of the pathogenesis of adverse cardiovascular outcomes in HIV- infected patients and test a novel approach for treating refractory hyperlipidemia.